Effects of Aclidinium Bromide in a Cigarette Smoke–Exposed Guinea Pig Model of Chronic Obstructive Pulmonary Disease

Abstract

Long-acting muscarinic antagonists are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of long-acting muscarinic antagonists have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS). We investigated the effects of aclidinium bromide on pulmonary function, airway remodeling, and lung inflammation in a CS-exposed model of COPD. A total of 36 guinea pigs were exposed to CS and 22 were sham exposed for 24 weeks. Animals were nebulized daily with vehicle, 10 μg/ml, or 30 μg/ml aclidinium, resulting in six experimental groups. Pulmonary function was assessed weekly by whole-body plethysmography, determining the enhanced pause (Penh) at baseline, after treatment, and after CS/sham exposure. Lung changes were evaluated by morphometry and immunohistochemistry. CS exposure increased Penh in all conditions. CS-exposed animals treated with aclidinium showed lower baseline Penh than untreated animals (P = 0.02). CS induced thickening of all bronchial wall layers, airspace enlargement, and inflammatory cell infiltrate in airways and septa. Treatment with aclidinium abrogated the CS-induced smooth muscle enlargement in small airways (P = 0.001), and tended to reduce airspace enlargement (P = 0.054). Aclidinium also attenuated CS-induced neutrophilia in alveolar septa (P = 0.04). We conclude that, in guinea pigs chronically exposed to CS, aclidinium has an antiremodeling effect on small airways, which is associated with improved respiratory function, and attenuates neutrophilic infiltration in alveolar septa. These results indicate that, in COPD, aclidinium may exert beneficial effects on lung structure in addition to its bronchodilator action.

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits

“…Present results on aclidinium are consistent with previous findings obtained in cigarette smoke-exposed guinea pigs [22] as well as in COPD patients [12,13] in whom aclidinium proved to have antitussive effects more intense than tiotropium. Apart from the study by Birrell et al [17] on guinea pigs, there are a few other investigations on the antitussive effects of tiotropium both in animal species [44] and patients [12,13,16,18,19].…”

“…In clinical studies, aclidinium provides greater improvements in COPD symptoms, including cough, than tiotropium and is well tolerated, with a similar safety profile [12,13]. A recent study in the guinea pig chronically exposed to cigarette smoke (an experimental model of COPD) indicates that aclidinium, in addition to beneficial effects on lung structure and function, shows a trend toward fewer cough episodes [22]. A comparative study on the antitussive effects of aclidinium and tiotropium in animal models is lacking.…”

Sildenafil in a cigarette smoke-induced model of COPD in the guinea-pig

“…Unrestrained whole-body plethysmography Respiratory function was measured weekly by unrestrained whole-body plethysmography (Buxco Research Systems, Wilmington, NC, USA) as previously described [19]. Breathing frequency, tidal volume (VT), minute ventilation (V′E) and respiratory resistance (enhanced pause (Penh)) [20] were recorded 10 min before exposure (baseline) and 10 min after CS or sham exposure.…”

Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling

“…It was shown in different animal models of COPD that neutrophilic inflammation induced by cigarette smoke or lipopolysaccharides (LPS) can be prevented by pretreatment with anticholinergics, including tiotropium [3,4], glycopyrrolate [21], and aclidinium [22]. Studies in muscarinic receptor subtype-deficient mice support a role for the M 3 receptor in inflammation in response to cigarette smoke [23].…”